Platelet-derived growth factor (PDGF) is a potent mitogen for mesenchymal cells. Two types (alpha and beta) of PDGF receptor have been cloned and sequenced. The ligand-binding region of the PDGF receptor is in the extracellular domain, which consists of five immunoglobulin-like regions. The cytoplasmic region of the PDGF receptor contains sequences homologous to other tyrosine kinases. The kinase sequences are interrupted by the kinase insert (KI) domain. The interaction of PDGF with its receptor causes some rapid changes in the cell, which include the activation of the receptor kinase activity. stimulation of several second messenger pathways and initiation of DNA synthesis. Both of the major in vivo and in vitro phosphorylation sites of betaPDGF receptor have been identified. We are studying the role of these phosphorylation sites of the alphaPDGF receptor in signal transduction. Several point mutations of the alphaPDGF receptor have been generated by site-directed mutagenesis. Mutation of the major autophosphorylation site, which lies in the second kinase domain, reduced the ability of PDGF-stimulated DNA synthesis. Mutation of the major in vitro phosphorylation site, which is in the kinase insert domain, does not affect the PDGF-induced DNA replication. However, the PDGF-induced PI3 kinase activity seem to be blocked by these mutant PDGF receptors.